PO.ET01.02 · 实验与分子治疗
TIP60在顺铂耐药的SCC中调控PTEN的表达、乙酰化和定位
TIP60 regulates PTEN expression, acetylation, and localization in cisplatin-resistant SCC
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
包括鳞状细胞癌（SCC）在内的非黑色素瘤皮肤癌（NMSC）仍然高度普遍，全球发病率逐年上升。顺铂是一种铂类化疗药物，常用于治疗晚期SCC和其他几种癌症。尽管许多患者最初有响应，但固有性或获得性耐药经常出现，限制了其临床疗效。TIP60是一种组蛋白乙酰转移酶，可修饰组蛋白和非组蛋白底物，在DNA损伤修复、细胞周期进程和凋亡中发挥关键作用。我们的研究表明，TIP60表达升高与SCC细胞系对顺铂耐药性增加相关。相反，肿瘤抑制因子PTEN对于维持受控的细胞生长和存活至关重要。PTEN的缺失、表达降低或错误定位会促进多种癌症类型的耐药、增殖和细胞存活增强。PTEN活性部分受乙酰化调控，我们实验室此前已表明ΔNp63alpha负向调控PTEN的表达和活性。我们假设TIP60通过抑制PTEN表达、或通过乙酰化修饰PTEN并改变其亚细胞分布来促进顺铂耐药。与该模型一致，我们发现与顺铂敏感的对应细胞系相比，顺铂耐药的SCC细胞系中PTEN水平显著降低。在耐药细胞中敲低TIP60可增加PTEN的转录本和蛋白水平，并增强PTEN启动子活性，支持了一种转录机制。TIP60敲低还降低了磷酸化Akt水平，而TIP60过表达则降低PTEN并增加磷酸化Akt。亚细胞分级分离表明，TIP60敲低增加了顺铂耐药细胞中细胞质PTEN。此外，TIP60敲低和药理学抑制均降低了PTEN乙酰化，提示存在一种翻译后调控模式。总之，这些发现支持这样一个模型：TIP60使PTEN乙酰化，并负向调控其总体和细胞质丰度，从而增强促存活的PI3K/Akt信号并促进顺铂耐药。阐明TIP60-PTEN轴的潜在机制可能揭示一个新的治疗易感性，以提高顺铂的有效性并支持其在SCC患者中的继续应用。
查看英文原文 English abstract
Non-melanoma skin cancers (NMSCs), including squamous cell carcinoma (SCC), remain highly prevalent, with global incidence rising each year. Cisplatin, a platinum-based chemotherapy drug, is commonly used to treat advanced SCC and several other cancers. Although many patients initially respond, intrinsic or acquired resistance frequently emerges, limiting its clinical efficacy. TIP60, a histone acetyltransferase that modifies both histone and non-histone substrates, plays key roles in DNA damage repair, cell-cycle progression, and apoptosis. Our research demonstrates that elevated TIP60 expression correlates with increased resistance to cisplatin in SCC cell lines. In contrast, the tumor-suppressor PTEN is essential for maintaining controlled cell growth and survival. Loss, decreased expression, or mislocalization of PTEN promotes drug resistance, proliferation, and enhanced cell survival across various cancer types. PTEN activity is regulated in part by acetylation and our lab has previously shown that ΔNp63alpha negatively regulates PTEN expression and activity. We hypothesize that TIP60 promotes resistance to cisplatin by suppressing PTEN expression, or modifying PTEN through acetylation, and altering its subcellular distribution. Consistent with this model, we found that PTEN levels were significantly reduced in cisplatin-resistant SCC cell lines compared with their cisplatin-sensitive counterparts. TIP60 knockdown in resistant cells increased PTEN transcript and protein levels, and enhanced PTEN promoter activity, supporting a transcriptional mechanism. TIP60 knockdown also reduced phosphorylated Akt levels, whereas TIP60 overexpression decreased PTEN and increased phosphorylated Akt. Subcellular fractionation demonstrated that TIP60 knockdown increased cytoplasmic PTEN in cisplatin-resistant cells. In addition, both TIP60 knockdown and pharmacological inhibition reduced PTEN acetylation, suggesting a post-translational mode of regulation. Together, these findings support a model in which TIP60 acetylates PTEN and negatively regulates its overall and cytoplasmic abundance, thereby enhancing pro-survival PI3K/Akt signaling and promoting cisplatin resistance. Defining the mechanisms underlying the TIP60-PTEN axis may uncover a novel therapeutic vulnerability to improve cisplatin effectiveness and support its continued use in SCC patients.
利益披露 Disclosure
C. McLaughlin, None..
A. Hira, None..
M. Kadakia, None.